Non-small cell lung carcinoma is responsible for approximately 85% of lung cancer and existing treatments for patients with advanced disease remain only marginally effective. Agents directed against the epidermal growth factor receptor have been developed (EGFR). However, only 10-20% of patients with relapsed non-small cell lung cancer have a partial or complete response to treatment with the common EGFR inhibitors, gefitinib and erlotinib. Point mutations and deletions in EGFR are associated with clinical responses to gefitinib in nearly all patients. Tumor cell lines with EGFR mutations are also sensitive to gefitinib treatment in vitro. This proposal is to further characterize the mutations in the EGFR in the tumors and tumor cell lines from subjects with non-small cell lung cancer. Aim 1 will be to establish the frequency and type of mutations in the epidermal growth factor receptor in previously untreated patients with advanced non-small cell lung cancer prospectively entered into trials using epidermal growth factor receptor inhibitors. We have two patient cohorts of 135 patients with advanced non-small cell lung cancer who are going to be studied. These cohorts will include those who respond to treatment, patients with stable disease, and patients with progressive non-small cell lung cancer. Aim 2 is to determine the relationship between epidermal growth factor receptor mutations, response to treatment, time to progression, and survival in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase. This will be done to determine if specific mutations give rise to different patient outcomes that include response, duration of response, and survival. We have assembled a consortium of investigators that have studied untreated patients with non-small cell lung cancer given single agent EGFR inhibitors to enable us to assemble multiple large groups of patients with responses and EGFR mutations. Aim 3 will be to study the tumors and tumor cell lines from patients with non-small cell lung cancer before and after treatment with EGFR inhibitors to determine the relationship between genetic changes and sensitivity and resistance to epidermal growth factor receptor inhibitors. NCI-H3255 and DFCI-LU- 011 are adenocarcinoma cell lines with EGFR mutations. Their sensitivity to EGFR inhibitors, downstream signaling events, and the mechanism of cell death compared to cell lines with wild type EGFR will be studied. These studies will provide guidance for future trials of EGFR inhibitors.